Diuretic combinations containing a thiazide and a mercurial



United States Patent Office 3,137,625 Patented June 16, 1964 3,137,625 DIURETHI COMBINATIONS ONTAENHNG A TiHAZIDE AND A MERCURlAL John H. Biel, Milwaukee, Wis, assignor to Lakeside Laboratories, Inc, Milwaukee, Wis, a corporation of Delaware 7 No Drawing. Filed Jan. 9, 1961, Ser. No. 81,244 4 Claims. (Cl. 167-65) This invention relates to the treatment of humans. More particularly, this invention is concerned with a novel method of inducing diuretic activity in humans, and novel pharmaceutical compositions useful therein.

There are on the market various diuretics of the thiazide type, viz., those containing the 7-sulfamoyl- 2H-1,2,4-benzothiadiaZine-l,l-dioxide or 7-sulfamoyl- 2H-3,4-dihydro-1,2,4-benzothiadiazine-1, l-dioxide nucleus, including chlorothiazide, dihydrochlorothiazide, dihydrofiumethiazide, benzydroflumethiazide, methylchlorothiazide and trichloromethiazide. Chlorothalidone (Hygroton, Ciba), while it contains a nucleus somewhat different than that of the thiazides just described is a sulfonamide-containing diuretic and for the purpose of this invention is to be considered Within the terminology used when thiazide diuretics are mentioned. Such compounds, and others of the thiazide type, are orally effective and increase diuretic activity in humans at daily dosage amounts of from about 4 to 300 mgm.

Although the thiazide type of diuretic is orally active and readily absorbed from the gastrointestinal tract, there are three major disadvantages involved with their use. The first is that the thiazide diuretics do not eliminate all of the excess fluid and sodium electrolyte but usually leave a 20% excess residue of sodium and water. They thus do not usually bring a cardiac patient down to dry Weight." This is particularly disturbing in the more severe cardiac patient. Due to the flat dose-response curve obtained with the thiazide type diuretics, not even larger dosages can rid the body of this excess residue. Secondly, thiazide diuretics eliminate not only excess sodium ion, which is desirable, but also increased amounts of potassium which in highly undesirable and can lead to death, in some cases, due to a potassium deficiency. Thirdly, prolonged administration of large doses of thiazide diuretics can produce a gouty arthritis which necessitates withdrawal of the drug.

In addition to the thiazide diuretics, available on the market various orally diuretics including Chlormerodrin (Neohydrin) and merbiurelidin (Meterox). Such mercurial diuretics suffer from relatively low absorption from the gastro-intestinal tract and therefore must be administered at a dose level which produces gastro-intestinal irritation and side effects.

According to the present invention it has been discovered that by concomitant, and advisably simultaneous, oral administration of a thiazide diuretic and a mercurial diuretic to a human there is achived a much greater, but unexpected, diuretic action than could be achieved by administering either of these drugs in the absence of the other. Furthermore, by administering a combination of a thiazide diuretic and a mercurial diuretic, lower amounts of each drug can be administered to a human than are needed when each drug is used separately to obtain an equal diuretic effect. As a result, the two drugs in combination can be administered at dosages substantially bethere are presently effective mercurial .mercurial diuretic effects the increased diuresis while actually reducing potassium excretion, thus greatly increasing the safety margin for this type of therapy. The mercurial diuretic apparently inhibits the increased potassium output normally produced by a thiazide diuretic. The combination of a thiazide diuretic and a mercurial diuretic thus provides safe, maximum diuretic therapy and sodium chloride excretion with a minimum of side effects and thus is a major advance in the treatment of congestive heart failure, edema, high blood pressure and glaucoma.

By using the diuretic combination of this invention the greatest reduction in amount of diuretic needed is in the mercurial component rather than in the thiazide. The gastro-intestinal side eflects incident to the higher mercurial dosage is thus essentially eleminated. However, the amount of mercurial used in the combination nevertheless suppresses the potassium excretion usually induced by the thiazide diuretic while simultaneously increasing diuresis over that obtainable by use of the thiazide alone.

The combination of a thiazide diuretic with a mercurial diuretic is advisably formulated into suitable pharmaceutical unit dosage forms such as tablets and capsules. Carriers can be used as desired to achieve a suitable volume to dosage relationship to facilitate ease of handlingthe unit dosage form. Such formulating is with in the skill of the pharmaceutical chemist.

The amount of thiazide diuretic and mercurial diretic used in the combination will be goverened by the activity of the particular drug used since the activity varies from one to the other. The following, however, are particular dosage combinations which can be used:

Trichloromethiazide 1 to 10 Chlormerodrin 1 to 30 Chlorothiazide 50 to 500 Chlormerodrin 1 to 40 Dihydrochlorothiazide 10 to Chlormerodrin 1 to 40 Dihydroflumethiazide 10 to 200 Chlormerodrin 1 to 40 Chlorthalidone 10 to 300 Chlormerodrin 1 to 40 Benzydrofiumethiazide 1 to 20 Chlormerodrin l to 40 Methylchlorothiazide 1 to 20 Chlormerodrin 1 to 40 (H) Trichloromethiazide 1 to 10 Merbiurelidin 1 to 40 A specific gelatin capsule could contain 4.0 mg. of trichloromethiazide and 18.5 mg. of chlormerodrin.

The diuretic activity of the novel combinations provided by this invention is illustrated by the results obtained with six normal human volunteers to Whom 4.0 mg. per day of trichloromethiazide was administered separately, and in combination with 1 8.5 mg. per day of chlormerodrin. The results of this first test, on an individual basis, are as follows with all determinations having been made on 24 hour urine samples:

Vol. Percent mEq Percent rnEq Percent (rnL) Vol. Na Na+ K K Change Change Change Control 1,365 189 70 Triehloromethiatide--- 1,585 +16 212 +12 71 +1 Chlormerodrin+ T'rif hloromethiaZide.-- 2,085 +52 323 +70 64 10 Control 1,820 203 o- 77 Trichloromethiazide 2,610 +44 283 +40 72 6 Chlorrnerodrin+ J grghloromethiazide--- 3,140 +72 319 +58 75 Control 2,045 204 93 Trichloromethiazide 2,165 +6 315 +54 110 +18 Chlormerodrh1+ C'i-Iiehl0romethiazide 2,730 +35 387 +00 101 +8 Control 1,165 130 80 'Irichloromethiazide.-- 1,360 +17 239 +85 120 +50 Ghlormerodrin+ AIri]e)hlororuethiazide 1,650 +43 214 +65 89 +11 Control 1,110 150 50 Trichloromethiazide 1,935 +72 261 +73 70 +40 Chlormerodrin+ 1jTri ohloromethiazide 1,720 +55 231 +54 60 +20 Control 3,060 196 89 Triehloromethiazide.-- 3,125 0 259 +30 116 +30 Ghlormerodrin+ Trichloromethiazide 4,305 +33 256 +30 106 +17 Subsequently, in a second test, the same six volunteers were administered the chlormerodrin (18.5 mg.) without the concomitant administration of trichloromethiazide. The results are as follows:

Vol. Percent mEq Percent mEq Percent (1111.) Vol. Na+ Na+ 11+ K+ Change Change Change Control 1,100 120.14 74.25

C lormcrodrin 1,025 156.83 +21 65.50 -12 Control.-. 1, 720 98. 73 4. 38. 70

Chlormerodrin. 1,225 0 105.47 +5 99. 59 +36 Control 1,590 113.37 57.72

Chlsormerodrim." 1,330 -16 129.64 +14 83.66 +45 ControL 3,165 178.82 75.96

Chlormerodrin 3,255 +3 130.20 -27 78.12 +4 The results of the first test show that the combination of trichloromethiazide and chlormerodrin achieved a much more marked increase in diuresis in all subjects except one than trichloromethiazide alone, and that the increase was obtained with a decrease in potassium output. In addition, in three of the six subjects there was also an increase in sodium excretion by use of the combination over trichloromethiazide alone.

The results obtained from the first test are even more surprising when it is considered that the 18.5 in". dose of chlormerodrin is one-third of the accepted daily dose of this drug when administered alone. At such a reduced dosage, side effects which occur with higher dosages, do not appear. Furthermore, a daily dose of 18.5 mg. of chlormerodrin alone is recognized to be insuflicient to significantly increase diuresis and this is shown in the second test. Thus, essentially no change in urine or sodium output resulted. With respect to potassium, two individuals had a significant increase in potassium output. Compared with the combination of trichloromethiazide and chlormerodrin, the potassium output appeared to be higher with chlormerodrin alone. Thus, chlormerodrin in non-diuretic doses potentiates the diuretic and natruiretic efiects of trichlorornethiazide, but at the same time inhibits potassium excretion.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit or" this invention, they are intended to be included Within the scope of the appended claims.

What is claimed is:

1. The method of increasing diuresis in a human while reducing potassium excretion caused by administration of a thiazide diuretic alone, and without producing the side effects caused by administration of an orally effective mercurial diuretic alone, which comprises orally administering to a human a combination of trichloromethiazide and chlormerodrin, said combination containing said trichloromethiazide in an amount effective to increase diuresis and containing the said chlormerodrin in an amount sufiicient to suppress potassium excretion induced by said trichloromethiazide but in an amount below that which causes sufficient adverse side efiects in the gastrointestinal tract.

2. The method of claim 1 wherein the amount of trichlorometbiazide is 1 to 10 mgs. and the amount of chlormerodrin is 1 to 30 mgs.

3. A pharmaceutical composition in unit-dosage form containing trichloromethiazide in an amount effective to increase diuresis in a human and chlormerodrin in an amount sufficient to suppress potassium excretion induced by said trichloromethiazide but in an amount below that which causes significant adverse side effects in the gastrointestinal tract, and a pharmaceutical carrier.

4. A pharmaceutical composition in unitdosage form containing from 1 to 10 mgs. of trichloromethiazide and 1 to 30 mgs. of chlormerodrin, and a pharmaceutical carrier.

References Cited in the file of this patent Clinical Medicine, October 1958, pp. 

1. THE METHOD OF INCREASING DIURESIS IN A HUMAN WHILE REDUCING POTASSIUM EXCRETION CAUSED BY ADMINISTRATION OF A THIAZIDE DIURETIC ALONE, AND WITHOUT PRODUCING THE SIDE EFFECTS CAUSED BY ADMINISTRATION OF AN ORALLY EFFECTIVE MERCURIAL DIURETIC ALONE, WHICH COMPRISES ORALLY ADMINISTERING TO A HUMAN A COMBINATION OF TRICHLOROMETHIAZIDE AND CHLOROMERODRIN, SAID COMBINTION CONTAINING SAID TRICHLOROMETHIAZIDE IN AN AMOUNT EFFECTIVE TO INCREASE DIURESIS AND CONTAINING THE SAID CHLORMERODRIN IN AN AMOUNT SUFFICIENT TO SUPPRESS POTASSIUM EXCRETION INDUCED BY SAID TRICHLOROMETHIAZIDE BUT IN AN AMOUNT BELOW THAT WHICH CAUSES SUFFICIENT ADVERSE SIDE EFFECTS IN THE GASTROINTESTINAL TRACT. 